Ebola hemorrhagic fever (EHF) and Marburg hemorrhagic fever (MHF) are rare viral diseases, endemic to central Africa. The overall burden of EHF and MHF is small in comparison to the more common protozoan, helminth, and bacterial diseases typically referred to as neglected tropical diseases (NTDs). However, EHF and MHF outbreaks typically occur in resource-limited settings, and many aspects of these outbreaks are a direct consequence of impoverished conditions. We will discuss aspects of EHF and MHF disease, in comparison to the "classic" NTDs, and examine potential ways forward in the prevention and control of EHF and MHF in sub-Saharan Africa, as well as examine the potential for application of novel vaccines or antiviral drugs for prevention or control of EHF and MHF among populations at highest risk for disease.

Viral Special Pathogens Branch, the Centers for Disease Control and
Prevention, Atlanta, Georgia, United States of America

University of Texas Medical Branch, United States of America

Correspondence: * E-mail: aho3@cdc.gov

Introduction

Ebola hemorrhagic fever (EHF) and Marburg hemorrhagic fever (MHF) are two similar
clinical diseases caused by viruses of the genera Ebolavirus (EBOV)
and Marburgvirus (MARV), respectively, both of the family
Filoviridae [1].
Owing to largely sensationalist accounts of outbreaks [2], these diseases are widely
recognized, despite the overall rarity of their occurrence [3]. However, EBOV and MARV are
highly pathogenic, and have traditionally been associated with devastating
outbreaks, with case fatality ranging from 25% to 90% [4]. Additionally,
EBOV and MARV are considered potential bioweapons agents [5], and as such are classified as
class A select agents. While the ability to conduct research on infectious EBOV and
MARV is limited to a small number of high containment laboratories, extensive
funding has been applied to primary research in the past decade, and progress has
been made in understanding the biology of these viruses, as well as toward
development of potential therapies [6], [7]. However, from the perspective of those at most risk of
disease, this progress has not been experienced. Large outbreaks of EHF in the
Democratic Republic of Congo (DRC) in 2007 and 2008, and in Uganda in 2007 [8]–[10], have
demonstrated the continued potential for prolonged virus transmission in
impoverished rural communities. We will discuss the epidemiology and control of EHF
and MHF, relative to the concepts of neglected tropical diseases (NTDs).

Epidemiology of Ebola and Marburg Hemorrhagic Fever

EBOV and MARV are zoonotic viruses, and outside of outbreaks, do not persist in human
populations. Current data suggest fruit bats as the reservoir of EBOV and MARV, and
the distribution of both viruses appears to be limited to sub-Saharan Africa [11]–[14] (with the
exception of Reston ebolavirus (REBOV), identified in the
Philippines, and not recognized to be associated with human disease [15], [16]). Clusters
and outbreaks are primarily the result of person-to-person transmission of these
viruses, which occurs through direct contact with the body, bodily fluids (commonly
to health care workers), or contaminated clothes or linens of an infected person
[17]–[21]. The level of viremia, and thus presumptively the risk of
transmission, corresponds with disease severity, with highest concentrations of the
virus during later stages of disease [22], [23].

Three distinct contact modalities account for virus transmission during outbreaks
(summarized in Table 1): 1)
transmission between family members, close contacts, and care givers of sick
individuals; 2) contact with dead bodies during preparation and funeral proceedings;
and 3) transmission in health care settings from sick patients to medical staff or
to other hospitalized patients by breaches in barrier nursing and reusing medical
equipment [18],
[19], [24]–[28]. As a result,
outbreak response involves three major components: 1) daily observation of all
contacts of sick individuals, so that upon onset of illness, persons can be
transported to medical facilities and avoid further transmission in the community;
2) ensuring safe burials of deceased individuals; and 3) establishment of patient
isolation wards, with medical staff equipped with and trained in usage of
personal-protective equipment, to block health care–associated transmission of
the virus [26],
[29]–[34].

While logistically challenging, the above interventions are not technologically
difficult. These have consistently been applied in outbreaks, and are effective in
stopping the chains of transmission. So why do large EHF and MHF outbreaks continue
to occur? Response activities are contingent on identification of the outbreak. A
common occurrence among large outbreaks is the large lag, often in the range of
months, between initial cases and actual detection of EBOV or MARV [35]. Typical
symptoms of EHF and MHF, such as fever, vomiting, diarrhea, fatigue, headache, and
myalgia [9],
[24], [25], [36], [37], can be
mistaken for other more frequent endemic tropical infections. However, the fact that
outbreaks occur most commonly in resource-limited settings should not be overlooked.
Other important aspects include limited capacity of medical and public health staff
to conduct disease surveillance and the inability to rapidly perform diagnostic
testing.

Additionally, while the zoonotic source of exposure is not always identified in
outbreaks, introductions of these viruses to human populations have been associated
with entering caves and mines (for MARV) and hunting for or processing bushmeat (for
EBOV) [38]–[45]. Educational interventions aimed at discouraging these
activities (or potentially directly blocking physical access to caves or mines) have
the potential to limit introduction of EBOV and MARV into human populations. For
instance, education outreach was performed in the border region of Republic of the
Congo (RoC) and Gabon after a series of EHF outbreaks occurred over numerous years,
starting in 1994; however, no outbreaks have occurred since 2005 [44]. Similarly,
introduction of MARV occurred for numerous years among miners in Watsa Zone of DRC
[39], and
cases of MHF ceased only following flooding of the mine [46]. Finally, among routes of
filovirus transmission to humans, it may be important to consider the role of other
potential secondary hosts. REBOV, and its association with primates from the
Philippines, was identified previously [47]. While serologic evidence
indicated that humans exposed to infectious primates may be infected, REBOV does not
appear to cause overt disease in humans [47], [48]. Interestingly, REBOV was
recently identified in commercial swine in the Philippines, and similarly, evidence
of seropositive humans exposed to these animals was observed [15]. Recent laboratory studies
have demonstrated that REBOV, as well as ZEBOV, not only infects, but also may be
transmitted among swine [49], [50]. The scenario that either a pathogenic filovirus may
enter (and be transmitted among swine) or that mutations in REBOV may result in a
virus pathogenic to humans should continue to be considered in global surveillance
efforts. In addition to the direct impact on human health, the potential economic
impact on agricultural production, if swine (or other livestock) are a direct or
perceived threat for transmission of filoviruses, would likely be devastating to a
local or regional economy.

Ebola and Marburg Hemorrhagic Fever as NTDs

Currently there is no standardized definition of an NTD [51], [52], and various groups have
applied differing standards in the classification of NTDs. Liese et al. summarized
two district approaches to characterizing NTDs, the first as “neglect as the
defining characteristic”, and the second as “the diseases' shared
features and their effects on poverty and development” [51]. The latter of these two
approaches has focused on a group of 13 specific protozoan, helminth, and bacterial
infections that have a large global burden of disease and strong poverty-promoting
effect, and persist as chronic infections despite effective medical treatments
available [53],
[54].
(Recently, proposals have expanded this list of NTDs to a total of 17 specific
infectious agents [55]).
Focusing on the former approach, an important aspect is the direct role of neglect
as a contributing factor to NTDs. Previous reviews have described the impact of NTDs
on the “bottom billion”, i.e., the portion of the human population
living in the most impoverished conditions [56]. Similarly, the “vicious
cycle” of interrelatedness between poverty and infectious diseases has been
noted by the World Health Organization (WHO) [57].

A major component of the “13 NTDs” is the underlying high burden of
disease, both from a morbidity and mortality standpoint, as well as from an economic
standpoint. One estimate suggests more than 500,000 deaths annually as a result of
these diseases [58]. The burden of EHF and MHF globally is substantially lower
(and in comparison to the economic impact of the 13 NTDs [59], the overall economic impact
of EHF and MHF would be marginal in comparison). To date, approximately 2,300 total
EHF and MHF cases have been recognized [3], [60]. There are some data to suggest
this number to be a substantial underestimate. Serosurveys in central Africa have
reported the prevalence of reactive antibodies to EBOV in human populations to range
from 5% to 15%, implying a much high burden of infection [61]–[63]. Since 1976,
in large outbreaks of EHF and MHF, the time from initial cases to outbreak
confirmation has typically taken months [35], [64]; thus, it is likely that
smaller, brief outbreaks or isolated cases frequently go unrecognized, especially in
remote areas. During an intense prospective surveillance program from 1981 to 1985
in the Sud-Ubangi region of northwestern DRC, Jezek et al. identified a total of 21
EHF cases, indicating a possible ongoing occurrence of sporadic EBOV infections in
this population [65]. Similarly, during an investigation of MHF in Watsa Zone
of northeastern DRC, which involved multiple zoonotic introductions in miners
working in gold mines (and some subsequent secondary transmissions) between 1998 and
2000, medical staff reported the disease as a locally recognized clinical entity in
miners, occurring as far back as possibly the 1980s [39]. Regardless, the overall burden
of disease due to EHF and MHF is clearly dwarfed in comparison to those of the 13
NTDs.

In contrast, when EHF and MHF are examined from a bottom billion viewpoint, there are
multiple factors supporting the notion that disease, and particularly outbreaks, are
components of impoverished conditions. From a geographic standpoint, the bulk of
human disease has occurred in rural, and often highly remote, locations in the
central African countries of Angola, Gabon, RoC, DRC, Sudan, and Uganda [4] (Figure 1), some of the least
developed locations in the world (for instance, see Table 2). As an example of remoteness,
71.3% of the Gulu, Uganda (site of the 2000 EHF outbreak), population live
more than 5 km from the nearest health facility, while this percentage is only
0.7% in the capital, Kampala [66]. Although the global
distribution of NTDs is more geographically widespread, multiple NTDs also have a
high prevalence across this region of Africa [53], [56].

Further defining the association between EHF and MHF and impoverished conditions is
the observation that amplification of EBOV and MARV transmission commonly occurs in
resource-limited health care settings. In addition to transmission associated with
re-used medical equipment, many outbreaks involve transmission (sometimes with high
frequency) to medical staff caring for patients [24]–[28]. Because EBOV and MARV
transmission occurs through direct physical contact with an infected person, bodily
fluids, or through contact with contaminated clothes or linens, transmission to
health care staff and patients can largely be controlled through implementation of
barrier nursing practices for individuals with hemorrhagic symptoms and ensuring
that needles or other medical equipment that may contain contaminated fluids are not
reused.

Although EHF and MHF may not have the regional or national poverty-promoting effects
as some NTDs, the local effects of an outbreak on a village, town, or region can be
devastating. Tens to hundreds of deaths have occurred in previous outbreaks.
Additionally, these conditions are highly stigmatizing [67]–[69]. Sick patients, medical staff,
as well as those who have recovered, commonly face fear and rejection or
stigmatization from the local community. Furthermore, the long-term health and
psychosocial impacts of EHF and MHF on survivors can be challenging; studies
demonstrate post-infection sequelae, as well as prolonged poor health, among those
who survived EBOV or MARV infection [69]–[74].

The impact of EHF or MHF on local health systems can be similarly devastating,
particularly for individuals in needs of standard medical care not associated with
hemorrhagic fever. In the series of Durba-Watsa MHF cases associated with the Durba
mine in northwest DRC, the only physician available at Watsa (district) hospital
died of presumed MHF in 1994 and no physician was available in the district from
1994 to 1996. A second physician died of MHF in 1999, again leaving the hospital
with no available physician. Similarly, the medical director and 11 staff members
for a major hospital died of EHF in the Gulu, Uganda, outbreak in 2000 [75], [76]. Beyond the
deaths of specific individuals, outbreaks have also had severe effects on the actual
functioning of medical services. For instance, the Kikwit, DRC, EHF outbreak in 1995
resulted in the infection of 80 health care workers and the closure of Kikwit
General Hospital for non-EHF related activities, severely limiting the availability
of medical care to the population of Kikwit (200,000), as well as surrounding areas
[26], [29].

An additional defining characteristic of the 13 NTDs is the absence of an available
vaccine [77].
Moran et al. previously noted that funding for development of pharmaceutical tools
for prevention or treatment is limited for many of the NTDs. For instance, of 2.5
billion US dollars devoted to research and development of new neglected disease
products, almost 80% was applied to HIV, tuberculosis, and malaria, with
approximately 2% devoted to helminths, and less than 0.1% devoted to
Buruli ulcer or trachoma [78]. Regardless, pharmaceutical treatments and cost effective
control measures are available for most NTDs [53], [56], underscoring a need for
improved implementation of treatment and control efforts. Even in the absence of a
vaccine, cases of dracunculiasis (guinea worm disease) have drastically declined
through basic public health measures, and guinea-worm eradication is anticipated in
the near future [79]. Similarly, no currently licensed vaccines or
therapeutics are available for EHF or MHF (discussed further below). While the
available funding for research and development of these products may contrast most
NTDs, the fact that effective public health measures to prevent or control EHF and
MHF are already known is consistent with the above observation for other NTDs.

Ways Forward

Improved Surveillance and Health Care Safety

As noted above, a common characteristic of large EHF and MHF outbreaks is the
break-down (or absolute lack of) public health surveillance, resulting in long
periods of time before identification of the outbreak by public health
authorities. With improved surveillance, early chains of transmission can be
identified and outbreak response efforts rapidly applied. As an example, during
the recent reemergence of EHF in Luwero district, Uganda (May 2011), viral
hemorrhagic fever was immediately suspected in the index (and only case) by
clinicians at the hospital. While in a rural area, Luwero is located less than 2
hours by vehicle from the capital of Uganda (Kampala). A confirmatory laboratory
diagnosis was acquired in less than a week, and outbreak response activities
commenced within 24 hours [80]. While contacts of this EHF case fortunately did not
develop disease, the ability to identify and follow-up all contacts would have
resulted in prevention of further spread of the virus, should secondary cases
have developed.

Public health approaches for NTDs have traditionally focused on vertical
drug-based treatment strategies [53], [54]. However, the importance of
integration of NTD control into broad health systems is now being recognized
[81], [82]. Moreover,
technical guidelines by the WHO Regional Office for Africa (AFRO) and Member
States were recently released for the Integrated Disease Surveillance and
Response (IDSR) strategy [83]. The IDSR recommends integrated surveillance of
multiple infectious diseases to broaden the ability to detect and respond to
infectious diseases of epidemic potential or those targeted for eradication or
elimination. Priority diseases included in the 2010 IDSR guidelines include EHF
and MHF, as well as a number of other NTDs, including Buruli ulcer,
dracunculiasis, leprosy, lymphatic filariasis, onchocerciasis, trachoma, and
trypanosomiasis. While public health resources are limited across sub-Saharan
Africa, and challenges still exist in its integration, studies have demonstrated
tangible improvement of surveillance as a result of IDSR implementation [84].

Laboratory diagnostics are a crucial component of public health surveillance, and
efforts need to be made to ensure capacity for rapid diagnostic testing for EHF
and MHF across sub-Saharan Africa, as well as the ability to rule out other
tropical infections. In the above noted EHF case in Uganda in May 2011,
in-country laboratory capacity was available, and a rapid diagnosis was made on
the index case, allowing for an immediate public health response [80].

Of additional importance to the control of EHF and MHF is the prevention of
health care–associated spread of the viruses. The fact that basic contact
precautions (gowns and gloves) can largely block spread of EHF and MHF in health
care settings underscores the effect of poverty on the spread of these diseases.
Efforts to provide greater availability of basic medical supplies to rural
health care settings in central Africa would help minimize the risk of large
outbreaks of EHF and MHF, as well as have the broad benefit of preventing
non-related health care–associated infections in patients and health care
workers, and ensure greater patient safety. A recent report by Marchal et al.
stressed potential linkages between NTD control and improvement of health
systems [82].
While infection control during medical care is only one aspect of the entire
health system, renewed focus on improving health systems may have a direct
impact on prevention of initial spread, and ultimately outbreaks, of EHF and
MHF.

Vaccines and Anti-Viral Therapies for EHF and MHF

Extensive research efforts over the past decade have focused on development of
vaccines and anti-viral therapies for EHF and MHF, and currently there are
numerous promising products in development [85]–[87]. This
evidence suggests there may be an optimistic picture for future licensing of
efficacious biologic-based measures for EHF and MHF. But are these applicable
for those most at risk for disease? There are two scenarios to consider:
vaccines that are administered before the exposure, which prevent disease, and
vaccines or anti-viral therapies that can be administered after the exposure
(either before or possibly after onset of disease) to prevent or improve the
clinical prognosis of illness. From an occupation-based risk standpoint,
prophylactic vaccination will be clearly a valuable preventive measure, both for
individuals with potential exposure in the laboratory or through ecological
work, as well as medical and public health personal involved in hands-on
outbreak response activities.

When we consider those at risk of endemic exposure to EBOV or MARV—the
bottom billion—the potential value of prophylactic vaccination becomes
murky. A scenario in which one envisions applying vaccine across the entire
endemic population in sub-Saharan Africa is unrealistic. Given the total burden
of filovirus disease (∼2,300 total cases identified since 1967), attempting
the administration of millions of doses of vaccine has limited justification,
particularly considering the current ongoing challenge of establishing high
levels of coverage of routine immunizations in many endemic areas. For instance,
estimated coverage of polio and measles among 1-year-olds in Uganda in 2009 was
59% and 68%, respectably [88].

A second prophylactic vaccination strategy would be to apply a targeted or mass
vaccination campaign to an entire region, in the event of an outbreak. Given the
nature of the spread of EBOV and MARV in outbreak settings (chains of
person-to-person transmission), the efficacious outbreak control measure already
developed (contact tracing, isolation, and safe burials), and the scope of even
the largest outbreaks (Gulu, Uganda in 2000 with 425 EHF cases is the largest
known outbreak), the application of mass vaccination would not be an efficient
or cost effective control mechanism, and would likely draw resources and public
personnel away from outbreak control activities. Additionally, if vaccine is
administered to an exposed individual during the incubation period and disease
subsequently develops, there is a risk that those administering the vaccine will
be perceived by the local population as spreading the disease, which would
undermine efforts to further implement vaccination or other control methods.

A final strategy, in the instance of a vaccine or anti-viral drug with the
potential to prevent or minimize severity of disease, would be to apply these
measures to high risk contacts of suspected or confirmed EHF or MHF cases, as
well as to those who are already ill (and in isolation). This activity, if
measures can be administered early enough to be effective, would inevitably save
lives and would be an incentive for suspected patients to enter isolation.
However, from an outbreak control standpoint, a symptomatic individual tracked
through contact tracing activities is in essence removed from the
“transmitter pool”, and shortly after onset of symptoms (and
infectiousness) will be placed under safe isolation for proper medical care.
Similarly, sick individuals, already in properly managed isolation, would not
further propagate the virus. Thus, while having potential therapeutic value,
post-exposure biologics may have limited impact on the scope of EHF or MHF
outbreaks.

Finally, it worth reiterating in the broad context of vaccines or anti-viral
therapies for outbreak settings, that any application is contingent on
identification of the outbreak. Since traditionally in large outbreaks, a high
proportion of cases occur before outbreak identification, biologic-based
prevention measures would have no impact on these cases. With effective
surveillance, initial cases can be identified rapidly, minimizing the overall
impact of the outbreak through classic outbreak control measures. Thus, while
not a stand-alone intervention for outbreak control, application of anti-viral
therapies may help lower the overall impact of fatalities in EHF and MHF
outbreaks.

Conclusions

Those most at risk for EHF and MHF are residents of rural central Africa, many of
whom are among the bottom billion. Outbreaks of EHF and MHF are commonly associated
with limited public health surveillance and inadequate medical preventive measures,
both partially the result of impoverished conditions. Effective methods to prevent
and control EHF and MHF are well understood. While challenging, efforts to combine
control of these diseases with other NTDs, through mechanisms such as integrated
surveillance and improvement of health systems, would provide a combined benefit to
populations in rural central Africa. While multiple candidate vaccines and
anti-viral therapies against EBOV and MARV are currently in development, classical
public health surveillance and outbreak control guidelines will likely remain the
cornerstone of disease control. However, modern therapies have the potential to
minimize the number of EHF and MHF deaths in outbreak settings.

The overall incidence of EHF and MHF is low; however, outbreaks can
have devastating local and regional consequences. EHF and MHF
outbreaks are facilitated by impoverished conditions, where
available public health and safe medical facilities are limited.

Integration of EHF and MHF surveillance and response into public
health systems for common NTDs may help in the control of both sets
of diseases.

Although vaccines may not prevent all future outbreaks, there are
promising vaccines for EHF and MHF on the horizon.

All funding was provided by the Centers for Disease Control and Prevention. The
funders had no role in study design, data collection and analysis, decision to
publish, or preparation of the manuscript.

We thank Craig Manning for mapping and graphical assistance.

Disclaimer: The findings and conclusions in this report are those of the authors and
do not necessarily represent the views of the Centers for Disease Control and
Prevention.

TDR/WHOYear: 2007Ten year vision strategy. Fostering an effective global research effort
on infectious diseases of poverty in which disease endemic countries play a
pivotal roleGenevaTDR/World Health Organization

Community transmission to family members and other
close contacts of EHF or MHF cases

Daily monitoring of all contacts of EHF and MHF cases
and rapid transfer of sick contacts to medical facility for
evaluation

Contact with deceased EHF or MHF cases during
preparation of the body or funeral proceedings

Implementation of safe burial practices for all
deceased individuals

Transmission in the health care setting from EHF or MHF
cases to medical staff by direct contact or contact with bodily
fluids, or to other patients through contaminated medical
equipment

Establishment of isolation ward and provide clinical
care by medical staff with training specific to EHF and MHF
outbreaks

[TableWrap ID: pntd-0001546-t002]
doi: 10.1371/journal.pntd.0001546.t002. Table 2
Select economic and health indicators for countries with previous large
outbreaks of Ebola or Marburg hemorrhagic fever (total number of countries
which rank is based on).